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Developmental neurotoxicants target neurodifferentiation into the serotonin phenotype: Chlorpyrifos, diazinon, dieldrin and divalent nickel.

Publication ,  Journal Article
Slotkin, TA; Seidler, FJ
Published in: Toxicol Appl Pharmacol
December 1, 2008

Developmental exposure to organophosphates (OP) produces long-term changes in serotonin (5HT) synaptic function and associated behaviors, but there are disparities among the different OPs. We contrasted effects of chlorpyrifos and diazinon, as well as non-OP neurotoxicants (dieldrin, Ni(2+)) using undifferentiated and differentiating PC12 cells, a well-established neurodevelopmental model. Agents were introduced at 30 microM for 24 or 72 h, treatments devoid of cytotoxicity, and we evaluated the mRNAs encoding the proteins for 5HT biosynthesis, storage and degradation, as well as 5HT receptors. Chlorpyrifos and diazinon both induced tryptophan hydroxylase, the rate-limiting enzyme for 5HT biosynthesis, but chlorpyrifos had a greater effect, and both agents suppressed expression of 5HT transporter genes, effects that would tend to augment extracellular 5HT. However, whereas chlorpyrifos enhanced the expression of most 5HT receptor subtypes, diazinon evoked overall suppression. Dieldrin evoked even stronger induction of tryptophan hydroxylase, and displayed a pattern of receptor effects similar to that of diazinon, even though they come from different pesticide classes. In contrast, Ni(2+) had completely distinct actions, suppressing tryptophan hydroxylase and enhancing the vesicular monoamine transporter, while also reducing 5HT receptor gene expression, effects that would tend to lower net 5HT function. Our findings provide some of the first evidence connecting the direct, initial mechanisms of developmental neurotoxicant action on specific transmitter pathways with their long-term effects on synaptic function and behavior, while also providing support for in vitro test systems as tools for establishing mechanisms and outcomes of related and unrelated neurotoxicants.

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Published In

Toxicol Appl Pharmacol

DOI

EISSN

1096-0333

Publication Date

December 1, 2008

Volume

233

Issue

2

Start / End Page

211 / 219

Location

United States

Related Subject Headings

  • Tryptophan Hydroxylase
  • Toxicology
  • Time Factors
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin
  • Receptors, Serotonin
  • Rats
  • RNA, Messenger
  • Phenotype
  • PC12 Cells
 

Citation

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Slotkin, T. A., & Seidler, F. J. (2008). Developmental neurotoxicants target neurodifferentiation into the serotonin phenotype: Chlorpyrifos, diazinon, dieldrin and divalent nickel. Toxicol Appl Pharmacol, 233(2), 211–219. https://doi.org/10.1016/j.taap.2008.08.020
Slotkin, Theodore A., and Frederic J. Seidler. “Developmental neurotoxicants target neurodifferentiation into the serotonin phenotype: Chlorpyrifos, diazinon, dieldrin and divalent nickel.Toxicol Appl Pharmacol 233, no. 2 (December 1, 2008): 211–19. https://doi.org/10.1016/j.taap.2008.08.020.
Slotkin, Theodore A., and Frederic J. Seidler. “Developmental neurotoxicants target neurodifferentiation into the serotonin phenotype: Chlorpyrifos, diazinon, dieldrin and divalent nickel.Toxicol Appl Pharmacol, vol. 233, no. 2, Dec. 2008, pp. 211–19. Pubmed, doi:10.1016/j.taap.2008.08.020.
Journal cover image

Published In

Toxicol Appl Pharmacol

DOI

EISSN

1096-0333

Publication Date

December 1, 2008

Volume

233

Issue

2

Start / End Page

211 / 219

Location

United States

Related Subject Headings

  • Tryptophan Hydroxylase
  • Toxicology
  • Time Factors
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin
  • Receptors, Serotonin
  • Rats
  • RNA, Messenger
  • Phenotype
  • PC12 Cells